In vivo suppression of erythropoiesis by tumor necrosis factor-alpha (TNF-alpha): reversal with exogenous erythropoietin (EPO).
Tumor necrosis factor-alpha (TNF-alpha) selectively kills tumor cells in vitro and in vivo and is being tested as a cancer therapeutic agent. We have shown that TNF-alpha significantly suppresses late-stage erythropoiesis, leading to anemia in chronically treated mice. These erythropoietic effects could limit the clinical use of TNF-alpha. Therefore, we have examined whether erythropoietin (EPO) could be used to prevent TNF-alpha-induced erythroid suppression. Normal mice were treated with a single dose of recombinant murine TNF-alpha (10(5) U/mouse, i.p.) with and without various concentrations of recombinant human EPO. After 3 days, effects on late-stage erythropoiesis were measured by determining the number of mature erythroid colony-forming cells (CFU-E) in the spleen and bone marrow. Simultaneous treatment with EPO abrogated the suppressive effect of TNF-alpha in a dose-dependent manner. EPO treatment also prevented the decrease in peripheral blood-hematocrit that was observed with chronic (5 x 10(4) U/mouse/day for 5 days) administration of TNF-alpha. TNF-alpha-induced hemorrhagic necrosis of tumors and stimulation of macrophage (CFU-M) progenitors were unaffected by EPO treatment. These results demonstrate that simultaneous injection of EPO can abrogate the TNF-alpha-induced suppressive effects on erythropoiesis.
Johnson
C S
CS
Laboratory of Experimental Hematology, AMC Cancer Research Center, Denver, CO 80214.
Cook
C A
CA
Furmanski
P
P
D000740:Anemia / Q000517:prevention & control; D000818:Animals; D004305:Dose-Response Relationship, Drug; D015672:Erythroid Precursor Cells / Q000187:drug effects; D004920:Erythropoiesis / Q000187:drug effects*; D004921:Erythropoietin / Q000494:pharmacology; D006400:Hematocrit; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D014409:Tumor Necrosis Factor-alpha; D004921:Erythropoietin